Probiotic Influences on Motor Skills: A Review

The effects of probiotics have mostly been shown to be favorable on measures of anxiety and stress. More recent experiments indicate single- and multi-strain probiotics in treating motor-related diseases. Initial studies in patients with Parkinson’s disease and Prader-Willi syndrome are concordant with this hypothesis. In addition, probiotics improved motor coordination in normal animals and models of Parkinson’s disease, multiple sclerosis, and spinal cord injury as well as grip strength in hepatic encephalopathy. Further studies should delineate the most optimal bacterial profile under each condition.


INTRODUCTION
Probiotics are defined as bacteria with favorable physiological properties and are designated as psychobiotics when they produce behavioral outcomes [1][2][3], the most important of which include Lactobacillus (L.) Bifidobacterium (B.), Streptococcus (S.), Escherichia (E.), Enterococcus (E.), and Clostridium butyricum [4].Most researchers in this field have focused attention on anxiety, stress, and depression via neurologic, endocrine, humoral, and immune systems [5][6][7][8].The brain is affected in the absence of microbiota in germfree animals.Effects on the brain were likewise noted after antibiotic administration.When bacterial strains, especially those deemed to be beneficial, were given to animals, neurobiological effects occurred, some of which also occurred in normal human subjects.Such studies were then extended to treat specific diseases.
The effects of gut microbiota were first evaluated in gastrointestinal diseases, cancer, obesity, and infections and then for neuropsychiatric symptoms [1][2][3][4][5][6][7][8].In particular, the treatment of liver disease and its neurological complications with antibiotics led to an understanding of the role of microbiota in other neurological conditions.Since the gut is innervated by the vagus nerve, several experimenters have aimed at deciphering whether microbiotic actions are transmitted via this pathway.At the present time, effects on animal and human behavior have mostly been analyzed for cognition *Address correspondence to this author at the Laboratory of Stress, Immunity, Pathogens (EA7300), Medical School, University of Lorraine, 54500, Vandoeuvre-les-Nancy, France; Tel: +33 (3) 83 15 42 56; Fax: +33 (3) 72 74 62 37; E-mail: lalondr54@gmail.comand emotion, to a lesser extent, sensorimotor functions.In the present review, we regard probiotic actions on sensorimotor functions under various neurologic conditions.Although most results are preliminary, this synthesis should be of use to guide future research.

Normal or Preterm Human Subjects
Probiotics undergo changes across the lifespan [9], so there is interest in investigating their effects in children up to old age.In a preliminary investigation of this kind, Bifidobacterium, Lactobacillus, and Coprococcus strains were more abundant in 18-month-old infants above the median in the fine motor skill subscore of the Bayley-III battery of neurodevelopment [10].It remains to be determined whether the administration of such strains increases motor skills in older children and adults.
In a double-blind, placebo-controlled, randomized trial, B. infantis BB-02 96579 + B. lactis BB-12 15954 + S. thermophilus TH-4 15957 had no effect on the Gross Motor Function Classification System score, the Bayley-III Motor Composite Scale, or the Movement Assessment Battery for Children in preterm children at 2-5 years of age [11].In a review of five papers, including the preceding one, Upadhyay [12] concluded that probiotics had no effect on motor behaviors in preterm children.exposed to treadmill exercise or not [13].The probiotic mixture increased cerebellar concentrations of gammaaminobutyric acid (GABA), the cerebellum being particularly relevant in performing this type of task [14].Likewise, L. fermentum JDFM216 increased latencies before falling from the rotorod and decreased foot slips from a stationary beam in 12-month-old mice [15].These results lend credence to the hypothesis that probiotics facilitate motor coordination and thus may be of use in sporting events [16].L. plantarum SPA3 + L. rhamnosus B-8238 counteracted the decrease in latencies before falling from the rotorod in antibiotic-induced dysbiosis in mice [17], indicating that individuals with suboptimal gut bacteria are more likely to improve with probiotics.
In an open-label, single-arm, baseline-controlled trial of patients with Parkinson's disease, L. plantarum PS128 improved the total score of the Unified Parkinson's Disease Rating Scale (UPDRS) and its akinesia subscore as well as a single index, mobility, and activities of daily living in the 39item Parkinson's Disease Questionnaire (PDQ-39) [32].Likewise, L. acidophilus + L. fermentum + L. reuteri + B. bifidum improved the total score of the UPDRS in a doubleblind trial [33].

Animal Models of Parkinson's Disease
L. acidophilus + L. plantarum + L. paracasei + L. delbrueckii subsp.bulgaricus + L. brevis + B. longum + B. breve + B. infantis + S. thermophilus, designated as SLAB51, was given before a unilateral 6-hydroxydopamine (6-OHDA) injection in the mouse striatum and improved the use of the contralateral forepaw in the cylinder test and postural asymmetry in the elevated body swing test [34].The supplement also counteracted 6-OHDA-induced decreases in tyrosine hydroxylase and dopamine transporter immunoreactivity in the substantia nigra, indicating preservation of dopaminergic neurons.Likewise, L. salivarius subsp.salicinius AP-32 increased locomotor speed and stride length while decreasing stance time in gait analyses of rats unilaterally injected with 6-OHDA along the nigro-striatal tract [35].The probiotic also increased the number of tyrosine hydroxylase-positive neurons in the substantia nigra and the striatum.In a similar manner, L. plantarum PS128 improved step adjustment in gait analyses of rats unilaterally injected with 6-OHDA along the nigro-striatal tract and increased tyrosine hydroxylase-positive neurons in the substantia nigra [36].In addition, 6-OHDA unilaterally injected in the substantia nigra followed by intraperitoneally administered apomorphine augmented contralateral rotations compared with controls and L. acidophilus + L. reuteri + L. fermentum + B. bifidum prevented these and increased the number of substantia nigra neurons destroyed by the neurotoxin [37].L. fermentum U-21 alone counteracted the paraquat-induced increase in latencies before descending from a vertical pole and the decrease in the number of tyrosine hydroxylase-positive neurons in the substantia nigra [38].
In addition to 6-OHDA, probiotics appear effective in counteracting anomalies caused by the peripheral injection of another dopamine neurotoxin, methyl-phenyl-tetrahydropyridine (MPTP).Indeed, L. plantarum CRL 2130 + S. thermophilus CRL 807 and CRL 808 decreased latencies before descending from the vertical pole and latencies before traversing the horizontal stationary beam and increased tyrosine hydrolase-positive cell counts in the substantia nigra of MPTP-injected mice [39].The same effects were found with Clostridium butyricum [40].Moreover, a mixture of L. lactis MG1363 + glucagon-like peptide-1 (GLP-1) reduced latencies before descending from the vertical pole and increased open-field activity in mice injected with MPTP as well as counteracting declines in the number of tyrosine hydroxylase-positive neurons in the substantia nigra [41,42].
In yet another Parkinsonian model, L. rhamnosis GG + L. rhamnosus + L. plantarum LP28 + L. lactis subsp.lactis + B. bifidum + B. longum reduced latencies before traversing the stationary beam and increased latencies before falling from the rotorod as well as improving gait patterns in MitoPark PD mice, characterized by inactivation of the Tfam (transcription factor A) mitochondrial gene in dopamine neurons [43].The mixture also added protective actions on substantia nigra dopamine neurons as determined by the number of tyrosine hydroxylase-positive cells.

Patients with Multiple Sclerosis
Motor dysfunctions, sometimes leading to paresis, figure as important features in the symptomatology of multiple sclerosis [44].Although there is doubt as to whether gut dysbiosis marks the cause or consequence of the disease, it has been considered a contributing factor [45][46][47][48][49]. Meta-analyses revealed the beneficial effects of probiotic supplementation on general health and depression in patients with multiple sclerosis [50][51][52].In a double-blind trial, L. reuteri + L. casei + L. plantarum + L. fermentum + B. infantis + B. lactis improved the global score of the Expanded Disability Status Scale (EDSS) and the General Health Questionnaire-28 (GHQ-28) in patients with multiple sclerosis, the former featuring the ability to walk [53].Further experiments must delineate whether this or other mixtures specifically improve motor scores.

Animal Models of Multiple Sclerosis
Antibiotics increased latencies before falling from the rotorod and improved axon damage in mice exposed to intracranial infection with Theiler's murine encephalomyelitis virus (TMEV), a model of multiple sclerosis [54], lending credence to the hypothesis that gut microbiota influences demyelinating diseases.In further support of this hypothesis, L. acidophilus DSM 24735 + L. paracasei DSM 24734 +L.
plantarum DSM 24730 + L. + L. bulgaricus DSM 24734 + B. infantis DSM 24737 + B. longum DSM 24736 + B. breve DSM 24732 + S. thermophiles DSM 24732, designated Vivomixx, increased latencies before falling from the rotorod and exhibited anti-inflammatory actions in TMEV-treated mice [55].Both the Vivomixx mixture and a 3-strain mixture of L. acidophilus LA 201 + L. salivarius LA 304 + B. lactis LA 304, designated Lactibiane iki, were examined in another murine model of multiple sclerosis: pertussis toxin-induced experimental autoimmune encephalomyelitis [56].As in the previous study, both probiotic mixtures increased latencies before falling from the rotorod.On the contrary, neither L. plantarum nor Bifidobacterium B94 had any effect on swimming speed in rats exposed to ethidium bromide-induced demyelination [57].In a third model of demyelination, the murine cuprizone-induced model, L. casei T2 augmented spontaneous alternation rates in a Y-maze [58], a measure of mental flexibility [59], so it remains to be determined whether these results can be generalized to motor coordination.More experiments are needed to determine whether motor signs should be included in the conclusions of a general review [60] and a meta-analysis [61] indicating probiotic-induced improvements on overall signs, body weight gain, and survival in experimental autoimmune encephalomyelitis.

Patients with Spinal Cord Injury
Gut microbiota may be an important factor in mediating neural repair following spinal cord trauma [62].In particular, spinal cord trauma may cause gut dysbiosis [63], so treating this condition becomes all the more relevant to the pathological process.Even with minimal actions on sensorimotor functions, psychobiotics may be of use in mitigating anxiety and depression [5][6][7].

Animal Models of Spinal Cord Injury
A mixture of broad-spectrum antibiotics worsened spinal cord pathology and slowed down recovery of locomotion in mice exposed to spinal cord trauma [64].Like control mice, antibiotic-treated mice eventually exhibited consistent plantar stepping but without forelimb/hindlimb coordination and were more prone to paw anomalies and trunk instability.Conversely, L. casei + L. plantarum + L. acidophilus + L. delbrueckii subsp.bulgaricus + B. longum + B. breve + B. infantis + S. salivarius subsp.thermophilus, designated VSL#3, promoted spinal cord recovery relative to the vehicle-treated group by increasing the frequency of plantar stepping and forelimb/hindlimb coordination along with improving paw position and trunk stability.The product also reduced lesion volume as well as axon and myelin pathology at the injury site.These data should encourage further analyses in the patterns of dysbiosis seen after spinal cord injury so that optimal probiotics are proposed.

Patients with Prader-Willi Syndrome
Prader-Willi syndrome is a disorder caused by the deletion of paternally expressed genes at the Chr.15q11.2-q13locus, resulting in hypotonia, developmental delay, hyper-phagia, obesity, and such neuropsychiatric signs as psychosis and compulsive behaviors [65].Gut microbiotas have been linked to Prader-Willi syndrome [66], so a randomized, double-blind, placebo-controlled trial of L. reuteri LR-99 was conducted [67].The probiotic improved the total score and fine motor skill subscore of the ASQ-3 test as well as the social communication subscore of the Gilliam Autism Rating Scale (GARS-3) while reducing body mass index.

Animal Models of Prader-Willi Syndrome
To our knowledge, a probiotic has yet to be examined in rodent models of Prader-Willi syndrome [68,69].

Patients with Hepatic Encephalopathy
Motor performance is impaired even in minimal hepatic encephalopathy [70].Neurocognitive scores in patients with hepatic encephalopathy were correlated with the presence of bacterial DNA [71] in line with the hypothesis that favorable bacteria are of use in treating this condition.Indeed, probiotics are useful in treating biochemical anomalies of hepatic encephalopathy [72][73][74][75].However, their use on human motor control has been left unexamined.

Animal Models of Hepatic Encephalopathy
The E. coli Nissle 1917 bacterium was genetically modified to consume and convert excessive ammonia to arginine and further modified to synthesize butyrate in rats with ligated bile ducts [76].When the engineered product synthesized arginine + butyrate, forelimb and hind-limb grip strength improved, but not latencies before falling from the rotorod.The combination of the antibiotic rifaximin, along with the Vivomixx probiotic mentioned above, was given in rats with ligated bile ducts, a model of type C hepatic encephalopathy [77].On magnetic resonance spectroscopy scans, duct ligation increased glutamine levels in the hippocampus and cerebellum, effects counteracted by rifaximin + Vivomixx, whereas the antibiotic alone was without effect.Duct ligation also decreased creatine levels in the cerebellum, an effect also counteracted by rifaximin + Vivomixx administration, while yet again, the antibiotic alone was without effect.Despite these favorable biochemical actions, there was no effect on bile duct ligation-induced hypoactivity in the open field.Further experimentation is required to determine whether probiotics specifically improve the sensorimotor impairment underlying hepatic encephalopathy.

CONCLUSION
Positive results have been obtained on the UPDRS in patients with Parkinson's disease given two Lactobacillus mixtures, data supported by those on three animal models measuring gait and motor coordination in vertical poles, stationary beams, and rotorod tests.One positive finding has been reported with L. reuteri on fine motor skills of the GARS-3 in Prader-Willi syndrome.But only experiments in mice or rats exist in regard to multiple sclerosis, spinal cord injury, and hepatic encephalopathy.In two models of multiple sclerosis, Lactobacillus combined with Bifidobacterium improved rotorod performance.Another mixture containing Lactobacillus and Bifidobacterium facilitated gait patterns in spinal cord injury.In hepatic encephalopathy, an improvement in grip strength was noted with E. coli.There is interest in extending such protocols with other motor-related diseases, such as spinocerebellar atrophy and amyotrophic lateral sclerosis.

FUNDING
The study was supported by EA7300.